There have already been reported several useful processes (for example, Japanese Unexamined Patent Publication No. 61-207373) for producing azetidinone derivatives represented by the general formula (1) (wherein OR1 is a protected hydroxyl group; R2 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group or a substituted or substituted aromatic group). In making an attempt to produce from such azetidinone derivatives of the general formula (1) substituted azetidinone derivatives represented by the general formula [3]: (wherein OR1 is as defined above; CO2R3 is an esterified carboxyl group; X and Y are the same or different and represent individually a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted alkenylthio group, a substituted or unsubstituted aralkylthio group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted silyloxy group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic-thio group, a substituted or unsubstituted heterocyclic-thio group, a substituted or unsubstituted acyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted thioester group, a substituted or unsubstituted amide group, substituted or unsubstituted amino group, a hydrogen atom or a halogen atom, or are taken together with each other to form a substituted or unsubstituted cycloalkan-2-on-1-yl group), it has been necessary to oxidize the sulfide group of the azetidinone derivative of the general formula (1) to thereby convert the group to the more readily removable sulfone group or to substitute the acyloxy group for the sulfide group.
In order to convert the azetidinone derivative of the general formula [1] to the corresponding sulfone-containing derivative, there is known a method utilizing peroxy acid (Yoshida et al., Chem. Pharm. Bull, 29, 2899 (1981)), while a method using a mercury compound (Yoshida et al., Chem. Pharm. Bull., 29, 2899 (1981)) is known for the conversion of the same to the acyloxy-containing derivative, but difficulties are encountered in bringing these methods into commercial practice in terms of hygiene, safety or toxicity and the like.
Referring to the conversion of (1) to the acyloxy derivative, there has recently been reported a useful method involving the use of a copper compound (Japanese Unexamined Patent Publication No. 3-163057), resulting in marked improvement in the commercial production of the said derivative. Nevertheless, this method requires heating in carrying out the reaction and is yet to be improved. On the other hand, there have been reported a method (Japanese Unexamined Patent Publication No. 3-157365) of directly converting the azetidinone derivative of the general formula [1] to the azetidinone derivative of the general formula [3]: (wherein OR1, CO2R3, X and Y are as defined above) and also a method (Ito et al., Tetrahedron, 47, 2801 (1991)) of converting an acryloxyacetidinone derivative to an azetidinone derivative of the general formula [3], which methods have been developed with a specific view to introducing a substituent into the 1-methylene group to enhance the chemical and in vivo stabilities of carbapenem based antimicrobial compounds. However, these methods do not allow the ester compound to be utilized directly as a substitution reagent; before the said reactions are carried out, the former requires the ester compound to be converted to the corresponding diazonium reagent, while the latter necessitates the conversion of the same to the oxazolidone reagent, respectively.
A method of converting the azetidinone derivative of the general formula (1) directly to the azetidinone derivative of the general formula [3] constitutes a process having one step less as compared with the method of converting the azetidinone derivative of (1) to the sulfone-containing or acyloxy-containing derivative to thereby effect the intended synthesis, and could consequently offer a useful, advantageous synthetic means, only if the method can be brought to practice by a simple and practical operation. If the method permits the reaction to be carried out at lower temperatures and can furthermore allow a readily available reagent to be used in the introduction of a substituent at the 1-methylene group directly without being converted to another reagent, in addition, substantial improvement could be achieved in practical aspects. In view of the above, the present inventors conducted investigation into a method permitting the azetidinone derivatives of the general formula [1] to be converted directly to the azetidinone derivative of the general formula [3] under mild conditions, and have found out the present invention.